tbuckley/cabot-search huggingface dataset:
CSIG-21. TITLE: INTEGRATIVE TRANSCRIPTOME PROFILING OF EXOSOME AND TISSUE IDENTIFIES PROGNOSTIC GENES AS THERAPEUTIC TARGETS OF GLIOBLASTOMA
Authors: Pallavi Goel, Vijay Laxmi Roy, Subhashini Sadasivam, Yashoda Ghanekar, Inderjeet Kaur, Vijay Sreegiriraju, Kiran Prathapa, Surya Madiraju, Amit Ray, Exsegen Neurosurgery Group
Journal: Neuro-Oncology (2023)

Abstract For glioma, molecular genetic analysis has grown in significant amounts for disease diagnosis and pathogenesis research. Due to limitations of tissue samples, liquid biopsy is being considered as a substitute for tissue biopsy which can be developed as a diagnostic technique. Studies have demonstrated that exosome-carrying molecules can foster a milieu that is favorable to cancer growth and therapy resistance. METHODS: In the present study the tumor tissue and serum of the same 80 patients were collected with a confirmed diagnosis of glioma with prior consent. Demographic details, pathology reports and survival data were also collected. RNA-seq analysis was performed in both tumor tissue and exosomal RNA. Fastq file with 100bp paired end reads were generated. Raw reads were trimmed using Trimmomatic (Version 0.39) to remove adapter sequences and low-quality reads. Reads mapping to ribosomal RNA were removed using SortMeRNA tool. Trimmed reads were then mapped to the human reference genome GRCh38.d1.vd1.fa using a two-pass method with STAR (2.7.10a). Differential gene expression was performed using DESeq2. The gene ontology and pathway analysis were performed using open source tool PANTHER. RESULTS: The differentially expressed genes shared between tumour tissue RNA and exosomal RNA experiments were selected for further analysis. Genes such as EGFR (tissue: Fold change (FC)[6.1], exosome: FC[7.2]; p-value&amp;lt; 0.001), PDFGRA (tissue: FC[3.7], exosome: FC[5.2]; p-value&amp;lt; 0.001), TTN (tissue: FC[12.6], exosome: FC[11.3]; p-value&amp;lt; 0.001) were found to be differentially regulated and were prominently associated with Integrin signaling pathway, Synaptic vesicle trafficking pathway, Wnt signaling and cellular proliferation. As per literature and clustering analysis, we found that these pathways and genes play an important role in the progression of tumors which can be further integrated into diagnostic platforms. CONCLUSION: This study will provide a reliable and effective way of diagnosis and management of glioma in patients with minimal invasion.
CNSC-38. CHARACTERIZATION OF THE FUNCTIONAL RELEVANCE OF INTRA- AND INTERTUMORAL NETWORKS IN PRIMARY BREAST CANCER
Authors: Christina Nürnberg, Katrin Schrenk-Siemens, Roberto Würth, Andreas Trumpp, Chanté Mayer, Matthia Karreman, Chenchen Pan, Wolfgang Wick, Frank Winkler
Journal: Neuro-Oncology (2023)

Abstract Despite intensive efforts to improve current therapeutical strategies, breast cancer continues to be a life-shortening diagnosis for a significant number of affected women. Considering that the innervation density of breast cancers negatively correlates with the prognosis, the emerging field of Cancer Neuroscience, which deals with the reciprocal interactions between the nervous system and cancer cells, represents an attractive novel research direction. In fact, studies on breast cancer brain metastases have proven that the metastatic cells receive growth stimuli by hijacking healthy glutamatergic synapses. Beyond being capable of forming direct glutamatergic cancer-neuron synapses, primary brain tumor cells also connect to a multicellular intercommunicating network that contributes to therapy resistance. Whether similar mechanisms also apply to tumors outside the brain – accountable for the majority of cancer cases – remains unknown. Here, we aim at unraveling the functional role of intratumoral networks and the influence of (potential) direct primary breast cancer cell-neuron interactions. We hypothesize that purinergic signaling as a universal synaptic signaling mechanism enhances tumor growth. Through the application of ex vivo whole-organ tissue-clearing and nerve-labeling approaches, we noticed prevalent sensory and sympathetic innervation in the healthy and diseased murine mammary gland. Furthermore, we measured tumor cell proliferation rates in an in vitro model of primary murine sensory DRG-neurons co-cultured with breast cancer stem cells and compared these to monoculture controls. By implanting a mammary imaging window over the growing primary tumor, we longitudinally track the calcium activity of breast cancer cells in their natural microenvironment in the living mouse. We thereby are able to record co-activity of neighboring cells indicative of intratumoral network communication in primary breast cancers. Overall, our data support the existence of functional intra- and intertumoral breast cancer cell networks as an alternative therapeutical target. Future work needs to concentrate on unequivocally detecting direct neuron-cancer cell contacts.
NCOG-21. TESTING AND VALIDATION OF A DIFFUSE GLIOMA COGNITIVE RESERVE MODEL
Authors: Kirsti Brandes, Jasleen Kaur, Shawn Hervey-Jumper
Journal: Neuro-Oncology (2023)

Abstract Behavioral and cognitive symptom severity varies widely across patients with glioma because of unknown mechanisms. The concept of cognitive reserve (CR) recognizes that there are individual differences in each person’s brain reserve capacity and this theory accounts for the common disconnection between the degree of brain injury and its symptom manifestations. CR is a fixed variable throughout an individual’s life and works by recruitment of dormant yet redundant neural networks, and by efficient information modulation. New strategies to treat cognitive impairments have been encumbered by a lack of models that accurately reflect human disease. Here, we measure the Cognitive Reserve Index (CRI) in a registry of 450 patients with WHO grade 2-4 glioma. Transient behavioral impairments were induced by anesthetic medications propofol, dexmedetomidine, and remifentanil during standard of clinical care. We administered and analyzed 48 picture naming (PN) and 32 auditory stimulus naming (AN) trials per patient both before and after drug administration with impairments defined as a decline in task performance by more than one standard deviation from the mean. We discovered that the CRI in patients with glioma follows a normal distribution, like the general US population. Next, we found a significant decline in task performance in a subgroup of patients in both PN and AN. Electrode arrays in vivo to record human local field potentials from glioma infiltrated cortex demonstrated electrophysiological biomarkers of cognitive decline. Further elucidation and validation of CR measures in patients may significantly influence the delivery and timing of cancer directed therapies.
NIMG-04. PRE-RADIATION PROGRESSION PREDICTION IN GLIOBLASTOMA PATIENTS
Authors: Walia Farzana, Mustafa M Basree, Norou Diawara, Zeina A Shboul, Sagel Dubey, Marie M Lockhart, Mohamed Hamza, Joshua Palmer, Khan M Iftekharuddin
Journal: Neuro-Oncology (2023)

Abstract Pre-Radiation Progression (PRP) has been identified as an increase ( &amp;gt; 25%) in the size of the residual brain tumor or interval development of a new tumor after surgical resection but prior to radiation therapy. Glioblastoma (GB) patients with PRP have worse survival outcome compared to patients without PRP (non-PRP).The standardized approach to identify PRP in GB patients is to manually compare early post-operative MRI to radiation planning MRI. In this study, we investigate the efficacy of traditional radiomics and sophisticated multi-resolution fractal texture features to differentiate PRP from non-PRP. Radiation-planning T1C magnetic resonance imaging (MRI) of 13 PRP and 13 non-PRP patients is analyzed to develop the classification method. For each patient, around 600 conventional radiomics and fractal texture features are obtained from tumor tissue and entire brain areas. We propose a two-step feature selection process followed by ensemble classification. In the first step of feature selection, we apply a beta-mixture based graphical model to identify correlations between the extracted features. The features are the nodes of the graph and the edges of the graph denote the correlations among the features and adjacency to PRP node. After the first step feature selection, the 21 selected features are used in the second step feature selection based on accuracy, similarity, and stability of each feature to yield the final 12 features. Lastly, we utilize the final 12 selected features for ensemble classification of PRP from non-PRP. With leave-one-out cross validation, the predictive model has an area under curve (AUC) of 0.79 and accuracy of 80% which indicates the discriminatory function of imaging features to differentiate PRP patients from non-PRP. The experimental results show the diagnostic ability of radiation planning imaging features to predict PRP from non-PRP.
CNSC-39. GENERATION AND CHARACTERIZATION OF LIVING ORGANOTYPIC BRAIN SLICE CULTURES AS A NOVEL PRE-CLINICAL MODEL FOR BRAIN CANCER
Authors: Rajaneekar Dasari, Breanna Mann, Xiaopei Zhang, Noah Bell, Adebimpe Adefolaju, Morrent Thang, Krishna Kanchi, Alain Valdivia, Yang Yang, Andrew Buckley, Vivien Lettry, Carolyn Quinsey, Yasmeen Rauf, David Kram, Noah Cassidy, Cyrus Vaziri, David L Corcoran, Stephen Rego, Yuchao Jiang, Lee M Graves, Denise Dunn, Scott Floyd, Albert Baldwin, Shawn Hingtgen, Andrew B Satterlee
Journal: Neuro-Oncology (2023)

Abstract A challenge in cancer research is developing reproducible, reliable, and practical models which can capture the complexity of cancer development and treatment. The development of functional precision medicine platforms is emerging as a promising strategy for improving pre-clinical drug testing and guiding clinical decisions. We have developed an organotypic brain slice culture (OBSC) technology composed of intact multicellular tissue which can be rapidly used for spatiotemporal drug response testing. OBSCs are reproducibly generated from Sprague-Dawley rat pups and used as living tissue substrates to culture treat different tumor cell lines and uncultured patient brain tumor resection tissue. We evaluated OBSC quality and reproducibility throughout the study by using a propidium iodide nuclear permeability assay. This technique enabled a broad dynamic range to distinguish between healthy and unhealthy slices. In these studies, the rat pup age at the time of generation had an impact on OBSC quality and quantity, indicating that OBSCs should be generated from eight-day-old pups. We also found that optimal OBSCs were generated using improved methods for brain dissection and OBSC culture conditions, establishing our robust, standardized procedure for OBSC generation. Following this optimization period, we continued to conduct quality control analysis with 6 OBSCs per batch for reproducibility. We also conducted immunohistochemistry analysis immediately after slicing and concluded that morphology of neurons in OBSCs remained unchanged between day 0 and 4. In addition, the activation of astrocytes attenuates by day 4 but persists in macrophages/microglia, suggesting that the myeloid cells can phagocytose dead cells and debris in OBSCs. In summary, these results indicate that the OBSC platform may be an effective model that accelerates preclinical drug testing and directs drug development towards clinical evaluation.
PATH-07. GENOMIC AND IMMUNE ANALYSIS OF PRIMARY REPLICATION-REPAIR DEFICIENT (RRD) GLIOMAS REVEALS THREE SUBGROUPS WITH DISTINCT DRIVERS AND RESPONSE TO IMMUNOTHERAPY: AN IRRDC REPORT.
Authors: Nicholas Fernandez, Yuan Chang, Caitlin Lee, Jose Dimayacyac, Adrian Levine, Logine Negm, Zoya Aamir, Liana Figueiredo Nobre, Vanessa Bianchi, Lucie Stengs, Owen Crump, Emma Gattoni, Jiil Chung, Nuno Nunes, Melissa Edwards, Eric Bouffet, Cynthia Hawkins, Anirban Das, Uri Tabori
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Replication-repair deficiency (RRD) caused by germline/somatic defects in mismatch repair (MMRD) and/or polymerase-proofreading genes (PPD) drives 5-10% of high-grade gliomas in children, adolescents, and young adults (CAYA). Despite harbouring high mutation-burden (TMB), the basis of their heterogenous responses to immune-checkpoint inhibitors (ICI) is unknown. METHODS We performed multi-omic and immune analyses on human RRD-glioma specimens and developed murine models to investigate their differential responses to ICI. RESULTS RRD-gliomas in 202 CAYA-patients uniformly harbored high genomic microsatellite-instability and hypermutation (median TMB: 302-mutations/megabase), with specific MMRD mutational signatures contributing to frequent mutations in TP53 (88%), ATRX (83%), RAS/MAPK (77%) and IDH1/2 (17%). Strikingly, common pediatric mutations (K27M, G34R/V and BRAF;p.V600E) unrelated to MMRD signatures were absent, and a unique methylation profile distinct from non-RRD gliomas was observed. Molecularly, RRD-gliomas segregated into three genomic subgroups: RRD1 (MMRD+PPD; 56%), RRD2 (MMRD-only; 27%), and RRD3 (MMRD+IDH1/2; 17%). RRD1 included glioblastomas that developed early in germline CMMRD patients across the cerebral hemispheres and posterior-fossa, harbored extreme TMB (median: 420-mutations/megabase), balanced copy-number profiles, and immunogenic PPD signatures. RRD3 predominated in Lynch syndrome, presented in older children, were located in the forebrain, harbored lower TMB (median: 31-mutations/megabase) and demonstrated specific chromosomal gains/losses. Enrichment for immune-resistant JAK-STAT signalling in the RRD2/RRD3 transcriptome, and presence of high CD8+ T-cells in RRD1-glioma microenvironment, correlated with significantly improved 24-month post-ICI survival of 75% in RRD1 versus 43% and 33% for RRD2/3, respectively (p &amp;lt; 0.0001). Genetically engineered mouse models recapitulated the immuno-genomic phenotype and ICI-responses of the human RRD-subgroups, allowing successful preclinical testing of combinatorial checkpoint-inhibition strategies. Significant temporal and spatial heterogeneity linked to genomic instability and post-therapy immune-escape were observed. CONCLUSION Our data emphasizes an immediate need to distinguish RRD-glioma subgroups in clinical practice and translate our preclinical discoveries to subgroup-specific ICI-based combinatorial clinical trials.
CSIG-23. PRIMARY CILIA DISRUPTION ALTERS THE TRANSCRITOME OF HUMAN GLIOBLASTOMA CELLS AND SUGGESTS NOVEL THERAPEUTIC STRATEGIES
Authors: Masahiro Oishi, Afua Agyeman-Andoh, Mi-Yeon Jung, Yeshavanth Banasavadi Siddegowda, Eric Burton, Desmond Brown
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Glioblastoma is the most common malignant primary brain tumor. Despite standard-of-care therapy with maximal safe resection, concomitant chemoradiation followed by adjuvant chemotherapy, median survival is 18 months, and 5-year survival is 6.8%. The genetic complexity, ability to suppress host immune surveillance, and the blood-brain-barrier all contribute to the uniform fatality of the disease. Primary cilia are microtubule-based organelles that protrudes from the apical surface of all mammalian cells. They regulate several canonical signal transduction cascades important for development and pathogenesis. Glioblastoma cells are ciliated although the tumor downregulate genes associated with cilia formation and function. Contemporary studies suggest that the regulation of ciliogenesis is an important prognostic consideration. In this study, human glioblastoma cells were modified through stable lentiviral transduction to downregulate KIF3A (a gene required for ciliogenesis), or AURKA (a component of the ciliary disassembly complex). We then performed deep transcriptomic sequencing to determine how the overall transcriptome of human glioblastoma cells change in response to cilia-targeted genetic manipulation. RESULTS High-resolution confocal microscopy demonstrated that cilia were absent in KIF3A knockdown cells but abundant following loss of AURKA. Functional loss of primary cilia was confirmed with Gli2A RT-PCR following treatment with SAG (SHH pathway activator). There appeared to be rearrangement of the transcriptome with ciliary loss. Ingenuity Pathway Analysis demonstrated that ciliary loss resulted in the activation of pathways of glioblastoma and other cancer signaling pathways, tumor immune microenvironment pathways, cytokine signaling, and actin cytoskeletal rearrangement among several others. CONCLUSION Loss of primary cilia in glioblastomas activate several pro-cancer and immunosuppressive pathways. This suggests that targeting of primary cilia may lead to simultaneous loss of multiple glioblastoma phenotypes that contribute to the tumor’s evolutionary advantage. This may result in a novel paradigm of ‘ciliotherapeutics’ for glioblastomas and other cancers.
PATH-17. PILOCYTIC ASTROCYTOMA EXHIBITING DIFFUSE LEPTOMENINGEAL DISSEMINATION: EXTREMELY RARE FORM OF LOW-GRADE GLIOMA WITH DICHOTOMOUS (CHILDREN VERSUS ADULTS) AND UNCHARACTERISTICALLY AGGRESSIVE BEHAVIOR
Authors: Nolan Brown, Cathleen Kuo, Yusuf Mehkri, Julian Gendreau
Journal: Neuro-Oncology (2023)

Abstract OBJECTIVE To identify all prior reports of pilocytic astrocytoma (PA) exhibiting diffuse leptomeningeal dissemination (LMD) (WHO Grade I) in an effort to comprehensively characterize this anomalous, predominantly pediatric pathology. METHODS A systematic review of the literature was performed using the PubMed, Scopus, and Web of Science databases. RESULTS Twenty-nine studies featuring 60 patients (54 pediatric,6 adult) were identified.The mean age at initial diagnosis was 10.2 ± 10.6 years (range, 0.3 to 55 years), and most of the patients were male (n=39,65.0%). The most common primary tumor locations were the hypothalamus (n=18,30.0%), cerebellum (n=16,26.7%), and optic chiasm (n=8,13.3%). Signs/symptoms at presentation included paralysis, cerebellar findings, and symptomatic, obstructive hydrocephalus. Most patients underwent surgery alone (n=26,43.4%) or in combination with radiotherapy (n=10,16.7%) or chemotherapy (n=8,13.3%). Of 43 patients who underwent surgery, subtotal resection (STR) was achieved in 26. STR appeared to be a risk factor for future LMD and poor prognosis. Additionally, adjuvant therapy did not seem to reduce the odds of subsequent LMD. Twenty-two patients (36.7%) were found to have LMD at presentation. Time to dissemination for the remaining patients ranged from between 3.6 - 206 months. Among all the included patients, 24 (40%) exhibited LMD within the brain only, 22 (36.7%) within the spine only, and 14 (23.3%) within both locations. Multi-agent chemotherapy alone (n=20, 33.3%) was the most commonly utilized treatment modality, followed by radiotherapy alone (n=13,21.7%), surgery with radiotherapy (n=10,16.7%), and surgery alone (n=5,8.3%). The mean follow-up duration was 44.2 ± 47.7 months (range, 0 to 221 months). Mortality occurred in 18 out of the 58 patients who had follow-up information available, with a mean time from LMD diagnosis to death of 19.9 ± 23.6 months. CONCLUSION Given its truly anomalous behavior, future concerted efforts to analyze the genetic profile of all identified tissue samples of PA with LMD is warranted.
TMIC-54. RADIOTHERAPY-INDUCED REMODELING OF THE GLIOBLASTOMA MICROENVIRONMENT
Authors: Rebecca Rosberg, Elinn Johansson, Crister Ceberg, Alexander Pietras
Journal: Neuro-Oncology (2023)

Abstract Radiotherapy (RT) is included in the standard of care for glioblastoma (GBM), and while primary tumors generally respond to RT, GBMs invariably recur as incurable lesions. We have previously demonstrated that RT generates a net tumor-supportive tumor microenvironment (TME), in part by inducing remodeling of the extracellular matrix, suggesting that there are therapeutic opportunities in targeting the altered TME of recurrent GBM. Here, we have used highly multiplexed immunohistochemistry in combination with single cell RNA sequencing to characterize the cellular composition and molecular alterations to the GBM TME as tumors progress from primary to irradiated to recurrent tumors, using a genetically engineered GBM mouse model. RT resulted in a phenotypic shift suggestive of a proneural-to-mesenchymal switch of lineage-traced tumor cells immediately after treatment, but proportions of tumor cell phenotypes were largely restored at the time of recurrence. Recurrent tumors displayed an altered immune landscape, as demonstrated e.g. by an increase in the proportion of CD8+ lymphocytes coupled to a decrease in the proportion of CD4+ cells. Together, our data suggest that RT remodels the GBM TME as well as alters the phenotype of bona fide glioma cells. Ongoing studies are aimed at understanding heterotypic cell-cell interactions unique to the irradiated and recurrent GBM TME.
NIMG-82. FET PET SENSITIVITY IN PRIMARY BRAIN TUMORS ACCORDING TO CNS WHO 2021: VALUE AND PITFALLS IN PRESURGICAL IMPLEMENTATION
Authors: Christoph Oster, Tobias Blau, Kathy Keyvani, Teresa Schmidt, Lazaros Lazaridis, Sarina Agkatsev, Ulrich Sure, Christoph Kleinschnitz, Björn Scheffler, Francesco Barbato, Ken Herrmann, Sied Kebir, Martin Glas
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND FET-PET imaging has emerged as a valuable tool in the characterization of unclear brain lesions that cannot be clearly diagnosed with conventional diagnostic methods. In 2021, the Central Nervous System (CNS) World Health Organization (WHO) introduced significant changes in the classification of CNS tumors. Notably, under the new classification, certain cases of WHO grade II glioma may be reclassified as glioblastoma. Unfortunately, a subset of grade II gliomas, as defined by the 2016 WHO classification, may exhibit no detectable FET uptake and lack contrast enhancement on MRI, which can lead to underestimation of such tumors and potentially result in inappropriate treatment decisions, including avoiding surgery. Question: In how many cases did the diagnostics consisting of MRI and FET PET underestimate the malignancy in unclear brain lesions? METHODS In this study, we conducted a retrospective analysis of all patients who underwent FET PET imaging of the brain between 2017 and June 2021, prior to their first surgical brain intervention. We obtained the results from presurgical MRI-scans and categorized the lesions based on whether they exhibited contrast media enhancement or not, in addition to the postsurgical molecular-histopathologic diagnosis. Our analysis focused on identifying the number of cases in which the diagnosis of malignancy was underestimated in the context of the WHO 2016 classification. To further investigate these cases, we conducted NGS and 850k-analysis to reclassify the results in accordance with the new CNS WHO 2021 classification. RESULTS After enrolling 85 patients, our study found that according to the 2016 classification, preoperative imaging underestimated malignancy in 14 cases (16%) where histopathological analysis revealed high-grade malignant brain tumors. In 32 cases (27%), the preoperative imaging correctly suggested a malignant tumor, which was later confirmed by histopathological analysis after surgery. The final results of this reclassification after the CNS-WHO-2021 will be presented at SNO-meeting.
NIMG-60. PATTERNS OF PROGRESSION IN GLIOBLASTOMA PATIENTS UNDERGOING IMMUNE CHECKPOINT INHIBITOR THERAPY
Authors: Adrien Rochand, Capucine Baldini, Mehdi Touat
Journal: Neuro-Oncology (2023)

Abstract Glioblastoma (GBM) is the most common primary brain neoplasm with a median survival of 15 months. This retrospective study investigated the patterns of radiologic progression in GBM patients treated with immune checkpoint inhibitors (ICI). Among 16 patients, PseudoProgression (PsPD) was observed in 43% and Hyperprogression (HPD) in 19% of cases. Patients with PsPD had an overall survival of 17.6 months versus 2.9 months for HPD. Identifying these atypical responses early is crucial for optimizing treatment strategies and patient selection. Further research is needed to identify prognostic indicators and biomarkers for immunotherapy efficacy in GBM.